Targeted drug delivery in which a bioactive agent (e.g., a drug or a therapeutic) is provided in an active state to a subject's system at effective concentrations is a long sought goal. Many difficulties must be overcome to reach this goal. For instance, an agent must first be successfully delivered internally, and the human body has developed many barriers to prevent the influx of foreign substances. Primary delivery methods presently used include oral delivery and injections. Both methods must overcome structural components that prevent delivery including the dermal barrier and the gastrointestinal lining. However, injections are painful, oral delivery often leads to gastrointestinal distress, and both methods tend to provide bursts of agents rather than a preferred steady-state delivery.
Transdermal delivery materials have been developed in an attempt to provide a painless route for successful delivery of active agents over a sustained period. In order to be successful, a transdermal scheme must deliver an agent across the epidermis, which has evolved with a primary function of keeping foreign substances out. The outermost layer of the epidermis, the stratum corneum, has structural stability provided by overlapping corneocytes and crosslinked keratin fibers held together by coreodesmosomes and embedded within a lipid matrix, all of which provides an excellent barrier function. Beneath the stratum corneum is the stratum granulosum, within which tight junctions are formed between keratinocytes. Tight junctions are barrier structures that include a network of transmembrane proteins embedded in adjacent plasma membranes (e.g., claudins, occludin, and junctional adhesion molecules) as well as multiple plaque proteins (e.g., ZO-1, ZO-2, ZO-3, cingulin, symplekin). Tight junctions are found in internal epithelium and endothelium (e.g., the intestinal epithelium, the blood-brain barrier) as well as in the stratum granulosum of the skin. Beneath both the stratum corneum and the stratum granulosum lays the stratum spinosum. The stratum spinosum includes Langerhans cells, which are dendritic cells that may become fully functioning antigen-presenting cells and may institute an immune response and/or a foreign body response to an invading agent.
Beyond the structural barriers to delivery of a bioactive agent, the body also has developed internal defense mechanisms, including the immune response and the foreign body response. Accordingly, even when a structural barrier has been breached, successful delivery of an agent requires avoidance of the internal defense mechanisms. When the body institutes an immune response and/or a foreign body response in an attempt to protect itself, the body's natural defenses will attempt to remove and/or destroy what is perceived as the invading agent. For successful systemic delivery, the bioactive agent must successfully enter the blood stream and pass through the lymph system, the liver, the spleen, etc. Identification of the bioactive agent as a foreign substance by the body's defenses will lead to at least partial removal of the agent from circulation, leading to lower levels of the agent remaining available for the desired use, i.e., lower bioavailability of the agent.
What are needed in the art are devices and methods that provide higher bioavailability of bioactive agents. More specifically, what are needed are devices and methods that can deliver a bioactive agent so as to successfully deliver the bioactive agent to the cardiovascular system and prevent targeting of the agent by the body's own defensive mechanisms.